The mammalian target of rapamycin (mTOR) plays a key role in tumour cell cycle
control, proliferation and survival, and has been implicated in resistance to endocrine
therapy in breast cancer. RAD001 (everolimus) is a novel macrolide that inhibits
mTOR and its downstream substrates in vitro. This study explores the use of
RAD001 at a dose of 5mg daily in women with early breast cancer.
31 postmenopausal women were given RAD001 for 14 days prior to primary surgical
intervention for early breast cancer. RAD001 was well tolerated in most patients, 5
did not complete treatment due to drug adverse effects.
Tumour samples before (pre) and after (post) 14 days treatment were assessed for
changes in proliferation and markers of the mTOR pathway. Significant reductions in
proliferation (Ki67) and oestrogen receptor (ER) expression were seen, and the
downstream effects of the mTOR pathway inhibited (p-S6 (ser235/236 and ser
240/244) and nuclear expression of p-Akt). Gene expression profiling from these
tumour samples has confirmed these findings, demonstrating reduction in expression
of proliferative genes and oestrogen dependence genes with RAD001 treatment.
The mTOR protein exists in two distinct complexes, raptor and rictor, and it has
previously been thought that mTOR inhibitors such as RAD001 only have effects
upon raptor. The implication of this if correct would be upregulation of Akt (Protein
Kinase B), which has been shown to be present in more aggressive and resistant
tumour types. The cell line study described herein has demonstrated no upregulation
in p-Akt expression with RAD001 treatment, and in one cell line inhibition of p-Akt
was sustained with prolonged cell treatment.